The overriding goal of this project is to provide a mechanistic understanding of how the immunologic responses to filarial parasites are controlled. The three major aspects of this project involved the parasite-specific immune responses in lymphatic filariasis and onchocerciasis in terms of regulation, protective immunity and the genetic underpinnings of these host responses. Parasite-specific anergy, a specific cellular unresponsiveness to filarial antigens (with responses to nonparasite antigens and mitogens remaining intact), is the hallmark of the immune response seen in asymptomatic individuals with the microfilaremic form of lymphatic filariasis, the clinical manifestation most commonly found in filarial-infected individuals. Previously, we had established that this hyporesponsive state was associated with a decreased frequency of antigen-reactive T and B cells and that this hyporesponsiveness was mediated through active downregulation by antigen-reactive cells that produced IL-10 and TGF-beta. Thus, the objective of the first part of the project was to identify the mechanisms by which this antigen-specific modulation of immune responsiveness was working. Previous studies carried out in both the Cook Islands, Guatemala, and Ecuador have identified groups of individuals who, despite lifelong residence in filarial-hyperendemic regions, remain infection free. These so-called putatively immune individuals likely provide the key to protective immunity in these infections and provide the rationale for studying both their immune responses and the antigens that induce them. Why different individuals develop different immunologic responses to filarial infection (and have different clinical outcomes as a consequence) is an important question that still has not been resolved. We are exploring the possible role of genetic factors or other mechanisms underlying the differential responsiveness to parasite antigen seen and at the same studying the relationship between maternal infection and subsequent clinical and immunological outcome.